Indane-amines as pd-l1 antagonists

ABSTRACT

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) 
     
       
         
         
             
             
         
       
     
     including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is an application claiming priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62/633,973 filed Feb. 22,2018, which is incorporated herein by reference in its entirety for allpurposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE DISCLOSURE

Programmed cell death protein-1 (PD-1) is a member of the CD28superfamily that delivers negative signals upon interaction with its twoligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed andexert a wide range of immunoregulatory roles in T cell activation andtolerance. PD-1 and its ligands are involved in attenuating infectiousimmunity and tumor immunity, and facilitating chronic infection andtumor progression.

Modulation of the PD-1 pathway has therapeutic potential in varioushuman diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011);350:17-37). Blockade of the PD-1 pathway has become an attractive targetin cancer therapy. Therapeutic antibodies that block the programmed celldeath protein-1 (PD-1) immune checkpoint pathway prevent T-cell downregulation and promote immune responses against cancer. Several PD-1pathway inhibitors have shown robust activity in various phases ofclinical trials (R D Harvey, Clinical Pharmacology and Therapeutics(2014); 96(2), 214-223).

Agents that block the interaction of PD-L1 with either PD-1 or CD80 aredesired. Some antibodies have been developed and commercialized. A fewpatent applications disclosing non-peptidic small molecules have beenpublished (WO 2015/160641, WO 2015/034820, and WO 2017/066227 andWO2018/009505 from BMS; WO 2015/033299 and WO 2015/033301 from Aurigene;WO 2017/070089, US 2017/0145025, WO 2017/106634, US2017/0174679,WO2017/192961, WO2017/222976, WO2017/205464, WO2017/112730,WO2017/041899 and WO2018/013789 from Incyte, WO2018/006795 fromMaxinovel and WO2018/005374 from us, ChemoCentryx). However there isstill a need for alternative compounds such as small molecules asinhibitors of PD-L1, and which may have advantageous characteristics interm of oral administration, stability, bioavailability, therapeuticindex, and toxicity.

BRIEF SUMMARY OF THE DISCLOSURE

In one aspect, provided herein are compounds having formula (I):

or a pharmaceutically acceptable salt thereof, or a prodrug orbioisostere thereof; wherein: R¹, R^(2a), R^(2b), R^(2c), R³, R⁴, R⁵,R^(6a), R^(6b), m, and n, are as defined herein.

In addition to the compounds provided herein, the present disclosurefurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods associated with preparation and useof such compounds. In some embodiments, the compounds are used intherapeutic methods to treat diseases associated with the PD-1/PD-L1pathway.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE DISCLOSURE Abbreviation and Definitions

The terms “a,” “an,” or “the” as used herein not only include aspectswith one member, but also include aspects with more than one member. Forinstance, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the agent” includes reference to one or more agents knownto those skilled in the art, and so forth.

The terms “about” and “approximately” shall generally mean an acceptabledegree of error for the quantity measured given the nature or precisionof the measurements. Typical, exemplary degrees of error are within 20percent (%), preferably within 10%, and more preferably within 5% of agiven value or range of values. Alternatively, and particularly inbiological systems, the terms “about” and “approximately” may meanvalues that are within an order of magnitude, preferably within 5-foldand more preferably within 2-fold of a given value. Numerical quantitiesgiven herein are approximate unless stated otherwise, meaning that theterm “about” or “approximately” can be inferred when not expresslystated.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon group,having the number of carbon atoms designated (i.e. C₁₋₈ means one toeight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl and3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. The term“cycloalkyl” refers to hydrocarbon rings having the indicated number ofring atoms (e.g., C₃₋₆cycloalkyl) and being fully saturated or having nomore than one double bond between ring vertices. “Cycloalkyl” is alsomeant to refer to bicyclic and polycyclic hydrocarbon rings such as, forexample, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The bicyclicor polycyclic rings may be fused, bridged, spiro or a combinationthereof. The term “heterocycloalkyl” or “heterocyclyl” refers to acycloalkyl group that contain from one to five heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Theheterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ringsystem. The bicyclic or polycyclic rings may be fused, bridged, spiro ora combination thereof. It is understood that the recitation for C₄₋₁₂heterocyclyl, refers to a group having from 4 to 12 ring members whereat least one of the ring members is a heteroatom. Non limiting examplesof heterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone,hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent group derived from an alkane, as exemplified by —CH₂CH₂CH₂CH₂—.Typically, an alkyl (or alkylene) group will have from 1 to 12 carbonatoms, with those groups having 8 or fewer carbon atoms being preferredin the present disclosure. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon group, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent group, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C═C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₆ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “hydroxyalkyl” or “alkyl-OH” refers to an alkyl group, asdefined above, where at least one (and up to three) of the hydrogenatoms is replaced with a hydroxy group. As for the alkyl group,hydroxyalkyl groups can have any suitable number of carbon atoms, suchas C₁₋₆. Exemplary hydroxyalkyl groups include, but are not limited to,hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1- or2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or3-position), and 2,3-dihydroxypropyl.

The term “C₁₋₃ alkyl-guanidinyl” refers to a C₁₋₃ alkyl group, asdefined above, where at least one of the hydrogen atoms is replaced witha guanidinyl group (—NHC(NH)NH₂).

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. It is understoodthat the recitation for C₅₋₁₀ heteroaryl, refers to a heteroaryl moietyhaving from 5 to 10 ring members where at least one of the ring membersis a heteroatom. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “carbocyclic ring,” “carbocyclic” or “carbocyclyl” refers tocyclic moieties with only carbon atoms as ring vertices. Carbocyclicring moieties are saturated or unsaturated and can be aromatic.Generally, carbocyclic moieties have from 3 to 10 ring members.Carbocylic moieties with multiple ring structure (e.g. bicyclic) caninclude a cycloalkyl ring fused to an aromatic ring (e.g.1,2,3,4-tetrahydronaphthalene). Thus, carbocyclic rings includecyclopentyl, cyclohexenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl. Theterm “heterocyclic ring” refers to both “heterocycloalkyl” and“heteroaryl” moieties. Thus, heterocyclic rings are saturated orunsaturated and can be aromatic. Generally, heterocyclic rings are 4 to10 ring members and include piperidinyl, tetrazinyl, pyrazolyl andindolyl.

When any of the above terms (e.g., “alkyl,” “aryl” and “heteroaryl”) arereferred to as ‘substituted’ without further notation on thesubstituents, the substituted forms of the indicated group will be asprovided below.

Substituents for the alkyl groups (including those groups often referredto as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety ofgroups selected from: —halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, unsubstituted C₁₋₈ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₈ alkyl, C₁₋₈ alkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-,6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. The term “acyl” as used by itself oras part of another group refers to an alkyl group wherein twosubstitutents on the carbon that is closest to the point of attachmentfor the group is replaced with the substitutent=O (e.g., —C(O)CH₃,—C(O)CH₂CH₂OR′ and the like).

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: —halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, andunsubstituted aryloxy-C₁₋₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The disclosure herein further relates to prodrugs and bioisosteresthereof. Suitable bioisosteres, for example, will include carboxylatereplacements (phosphonic acids, phosphinic acids, sulfonic acids,sulfinic acids, and acidic heterocyclic groups such as tetrazoles).Suitable prodrugs will include those conventional groups known tohydrolyze and/or oxidize under physiological conditions to provide acompound of Formula I.

The terms “patient” and “subject” include primates (especially humans),domesticated companion animals (such as dogs, cats, horses, and thelike) and livestock (such as cattle, pigs, sheep, and the like).

As used herein, the term “treating” or “treatment” encompasses bothdisease-modifying treatment and symptomatic treatment, either of whichmay be prophylactic (i.e., before the onset of symptoms, in order toprevent, delay or reduce the severity of symptoms) or therapeutic (i.e.,after the onset of symptoms, in order to reduce the severity and/orduration of symptoms).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentdisclosure contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer to the compound in which one of the isomers is present andsubstantially free of the other isomer. ‘Substantially free of’ anotherisomer indicates at least an 80/20 ratio of the two isomers, morepreferably 90/10, or 95/5 or more. In some embodiments, one of theisomers will be present in an amount of at least 99%.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed within the scope of the present disclosure.For example, the compounds may be prepared such that any number ofhydrogen atoms are replaced with a deuterium (²H) isotope. The compoundsof the present disclosure may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. Unnatural proportions of an isotope may be defined as rangingfrom the amount found in nature to an amount consisting of 100% of theatom in question. For example, the compounds may incorporate radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C), or non-radioactive isotopes, such as deuterium (²H) orcarbon-13 (¹³C). Such isotopic variations can provide additionalutilities to those described elsewhere within this application. Forinstance, isotopic variants of the compounds of the disclosure may findadditional utility, including but not limited to, as diagnostic and/orimaging reagents, or as cytotoxic/radiotoxic therapeutic agents.Additionally, isotopic variants of the compounds of the disclosure canhave altered pharmacokinetic and pharmacodynamic characteristics whichcan contribute to enhanced safety, tolerability or efficacy duringtreatment. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

Compounds

In one aspect, the present disclosure provides compounds having formula(I):

or a pharmaceutically acceptable salt thereof, or a prodrug orbioisostere thereof, wherein:

-   R¹ is selected from Formula (IIa) or Formula (IIb):

-   each of substitutents R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) is    independently selected from the group consisting of H, halogen, —CN,    —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a), —OC(O)NR^(a)R^(b),    —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c), —NR^(a)—C(O)NR^(a)R^(b),    —NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a), —O—X¹—CO₂R^(a),    —O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b), —X¹—CO₂R^(a),    —X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), wherein each X¹ is a    C₁₋₄ alkylene; each R^(a) and R^(b) is independently selected from    hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the    same nitrogen atom can be combined with the nitrogen atom to form a    five or six-membered ring having from 0 to 2 additional heteroatoms    as ring members selected from N, O or S, wherein the five or    six-membered ring is optionally substituted with oxo; each R^(c) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl and C₁₋₈ haloalkyl; and optionally when two    substituents are on adjacent carbon atoms of the benzene ring, they    may combine to form a fused five, six or seven-membered carbocyclic    or heterocyclic ring optionally substituted with from 1 to 3    substituents independently selected from halo, oxo, C₁₋₈ haloalkyl    and C₁₋₈ alkyl;-   L is a linking group selected from the group consisting of:

-   wherein each of the subscripts q is independently 1, 2, 3 or 4, and    L is optionally further substituted with one or two members selected    from the group consisting of halogen, hydroxy, C₁₋₃ alkyl, —O—C₁₋₃    alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H;-   Z is selected from the group consisting of azetidinyl, pyrollidinyl,    piperidinyl, morpholinyl, pyridyl, pyrimidinyl, guanidinyl,    quinuclidine, and 8-azabicyclo[3.2.1]octane, each of which is    optionally substituted with from 1 to 3 groups independently    selected from halogen, hydroxy, C₁₋₃ alkyl, —NH₂, —NHC₁₋₃alkyl,    —N(C₁₋₃alkyl)₂, —O—C₁₋₃ alkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ haloalkyl and    —CO₂H;-   or-   Z is selected from the group consisting of —CO₂R^(z1) and    —NR^(Z1)R^(z2); wherein R^(z1) is selected from the group consisting    of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈ hydroxyalkyl; and R^(z2)    is selected from —C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkyl-COOH, C₁₋₈    alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂, C₁₋₈ alkyl-PO₃H₂,    C₁₋₈ alkyl-C(O)NHOH, —C(O)—C₁₋₈alkyl-OH, —C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀    cycloalkyl, —C₃₋₁₀ cycloalkyl-COOH, —C₃₋₁₀ cycloalkyl-OH, C₄₋₈    heterocyclyl, —C₄₋₈ heterocyclyl-COOH, —C₄₋₈ heterocyclyl-OH, —C₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₅₋₁₀    heteroaryl and —C₁₋₈alkyl-C₅₋₁₀ heteroaryl;-   each R^(2a), R^(2b) and R^(2c) is independently selected from the    group consisting of H, halogen, —CN, —R^(d), —CO₂R^(e),    —CONR^(e)R^(f), —OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e),    —NR^(f)C(O)₂R^(d), —NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e),    —X²—OR^(e), —X²—NR^(e)R^(f), —X²—CO₂R^(e), —SF₅, and    —S(O)₂NR^(e)R^(f), wherein each X² is a C₁₋₄ alkylene; each R^(e)    and R^(f) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O and S, and optionally substituted with oxo; each R^(d) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl;-   R³ is selected from the group consisting of —NR^(g)R^(h) and C₄₋₁₂    heterocyclyl, wherein the C₄₋₁₂ heterocyclyl is optionally    substituted with 1 to 6 R^(3a);-   each R^(3a) is independently selected from the group consisting of    halogen, —CN, —R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH,    —C(O)R^(j), —OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k),    —CONHOH, —PO₃H₂, —NR^(j)—X³—C(O)₂R^(k), —NR^(j)C(O)NR^(j)R^(k),    —NR^(j)R^(k), —OR^(j), —S(O)₂NR^(j)R^(k), —O—X³—OR,    —O—X³—NR^(j)R^(k), —O—X³—CO₂R^(j), —O—X³—CONR^(j)R^(k), —X³—OR^(j),    —X³—NR^(j)R^(k), —X³—CO₂R^(j), —X³—CONR^(j)R^(k), —X³—CONHSO₂R^(j)    and SF₅; wherein X³ is C₁₋₆ alkylene and is optionally further    substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl    or CO₂H, wherein each R^(j) and R^(k) is independently selected from    hydrogen, C₁₋₈ alkyl optionally substituted with 1 to 2 substituents    selected from OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂, COO—C₁₋₈alkyl or    CO₂H, and C₁₋₈ haloalkyl optionally substituted with 1 to 2    substituents selected from OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,    COO—C₁₋₈alkyl or CO₂H, or when attached to the same nitrogen atom    R^(j) and R^(k) can be combined with the nitrogen atom to form a    five or six-membered ring having from 0 to 2 additional heteroatoms    as ring members selected from N, O or S, and optionally substituted    with oxo; each R^(i) is independently selected from the group    consisting of —OH, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl each    of which may be optionally substituted with OH, SO₂NH₂, CONH₂,    C(O)NHOH, PO₃H₂, COO—C₁₋₈-alkyl or CO₂H;-   R^(g) is selected from the group consisting of H, C₁₋₈ haloalkyl and    C₁₋₈ alkyl;-   R^(h) is selected from —C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈    hydroxyalkyl, C₁₋₈alkyl-CO₂R^(j), C₁₋₈alkyl-CONR^(j)R^(k), and    C₁₋₈alkyl-CONHSO₂R^(j), C₁₋₈ alkyl-SO₂NR^(j)R^(k), C₁₋₈ alkyl-PO₃H₂,    C₁₋₈ alkyl-C(O)NHOH, C₁₋₈ alkyl-NR^(h1)R^(h2), —C(O)R, C₃₋₁₀    cycloalkyl, —C₃₋₁₀ cycloalkyl-COOR^(j), —C₃₋₁₀ cycloalkyl-OR^(j),    C₄₋₈ heterocyclyl, —C₄₋₈ heterocyclyl-COOR^(j), —C₄₋₈    heterocyclyl-OR^(j), —C₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C(═O)OC₁₋₈    alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀ cycloalkyl, C₅₋₁₀    heteroaryl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, —C₁₋₈ alkyl-C₆₋₁₀ aryl,    —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —CO₂—C₁₋₈ alkyl-O₂C—C₁₋₈ alkyl, —C₁₋₈    alkyl-NH(C═O)—C₂₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl, —C₁₋₈    alkyl-NH(C═O)—C₂₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈    alkyl-COOR^(j), and —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OR^(j)    optionally substituted with CO₂H; or    -   R^(h) combined with the N to which it is attached is a mono-,        di- or tri-peptide comprising 1-3 natural amino acids and 0-2        non-natural amino acids, wherein    -   the non-natural aminoacids have an alpha carbon substituent        selected from the group consisting of C₂₋₄ hydroxyalkyl, C₁₋₃        alkyl-guanidinyl, and C₁₋₄ alkyl-heteroaryl,    -   the alpha carbon of each natural or non-natural amino acids are        optionally further substituted with a methyl group, and    -   the terminal moiety of the mono-, di-, or tri-peptide is        selected from the group consisting of C(O)OH, C(O)O—C₁₋₆ alkyl,        and PO₃H₂, wherein    -   R^(h1) and R^(h2) are each independently selected from the group        consisting of H, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl;    -   the C₁₋₈ alkyl portions of R^(h) are optionally further        substituted with from 1 to 3 substituents independently selected        from OH, COOH, SO₂NH₂, CONH₂, C(O)NHOH, COO—C₁₋₈ alkyl, PO₃H₂        and C₅₋₆ heteroaryl optionally substituted with 1 to 2 C₁₋₃        alkyl substituents,    -   the C₅₋₁₀ heteroaryl and the C₆₋₁₀ aryl portions of R^(h) are        optionally substituted with 1 to 3 substituents independently        selected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,        COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂,        C₁₋₄alkyl CONH₂, C₁₋₄alkyl-C(O)NHOH, C₁₋₄alkyl-PO₃H₂,        C₁₋₄alkyl-COOH and phenyl, and    -   the C₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkyl portions of R^(h) are        optionally substituted with 1 to 4 R^(w) substituents;-   each R^(w) substituent is independently selected from C₁₋₄ alkyl,    C₁₋₄ alkyl-OH, C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂,    C₁₋₄ alkyl-C(O)NHOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈ alkyl, COOH,    SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂ and oxo;-   R⁴ is selected from the group consisting of O—C₁₋₈ alkyl, O—C₁₋₈    haloalkyl, C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄ alkyl-C₄₋₇    heterocycloalkyl, —O—C₁₋₄ alkyl-C₆₋₁₀aryl and —O—C₁₋₄ alkyl-C₅₋₁₀    heteroaryl, each of which is optionally substituted with 1 to 5    R^(4a);-   each R^(4a) is independently selected from the group consisting of    halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(P), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(P), —NR^(n)R^(P), —OR^(n), —O—X⁴—OR^(n),    —O—X⁴—NR^(n)R^(P), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(P), —X⁴—OR^(n),    —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅,    —S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), C₃₋₇ cycloalkyl and C₄₋₇    heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings    are optionally substituted with 1 to 5 R^(t), wherein each R^(t) is    independently selected from the group consisting of C₁₋₈ alkyl,    C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n),    —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(p), —NR^(n)C(O)₂R^(m),    —NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(p), —OR^(n), —O—X⁴—OR^(n),    —O—X⁴—NR^(n)R^(P), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(P), —X⁴—OR^(n),    —X⁴—NR^(n)R^(P), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅, and    —S(O)₂NR^(n)R^(p);-   wherein each X⁴ is a C₁₋₆ alkylene; each R^(n) and R^(P) is    independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈    haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(m) is    independently selected from the group consisting of C₁₋₈ alkyl, C₂₋₈    alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(4a)    substituents are on adjacent atoms, they are combined to form a    fused five or six-membered carbocyclic or heterocyclic ring    optionally substituted with oxo;-   the subscript n is 0, 1, 2 or 3;-   each R⁵ is independently selected from the group consisting of    halogen, —CN, —R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r),    —OC(O)NR^(r)R^(s), —NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q),    —NR^(r)—C(O)NR^(r)R^(s), —NR^(r)R^(s), —OR^(r), —O—X⁵—OR^(r),    —O—X⁵—NR^(r)R^(s), —O—X⁵—CO₂R^(r), —O—X⁵—CONR^(r)R^(s), —X⁵—OR^(r),    —X⁵—NR^(r)R^(s), —X⁵—CO₂R^(r), —X⁵—CONR^(r)R^(s), —SF₅,    —S(O)₂NR^(r)R^(s), wherein each X⁵ is a C₁₋₄ alkylene; each R^(r)    and R^(s) is independently selected from hydrogen, C₁₋₈ alkyl, and    C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can be    combined with the nitrogen atom to form a five or six-membered ring    having from 0 to 2 additional heteroatoms as ring members selected    from N, O or S, and optionally substituted with oxo; each R^(q) is    independently selected from the group consisting of C₁₋₈ alkyl, and    C₁₋₈ haloalkyl;-   R^(6a) is selected from the group consisting of H, C₁₋₄ alkyl and    C₁₋₄ haloalkyl;-   the subscript m is 0, 1, 2, 3 or 4;-   each R^(6b) is independently selected from the group consisting of    F, C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each    R^(u) and R^(v) is independently selected from hydrogen, C₁₋₈ alkyl,    and C₁₋₈ haloalkyl, or when attached to the same nitrogen atom can    be combined with the nitrogen atom to form a five or six-membered    ring having from 0 to 2 additional heteroatoms as ring members    selected from N, O or S, and optionally substituted with oxo.

In some embodiments, the present disclosure provides compounds havingthe formula formula (Ia) or (Ib):

In some selected embodiments, the compounds of formula (I), (Ia) or (Ib)are those compounds wherein R¹ is selected from the group consisting of:

In some selected embodiments, the compounds of formula (I), (Ia) or (Ib)are those compounds wherein R¹ is selected from the group consisting of:

In some selected embodiments, the compounds of formula (I), (Ia) or (Ib)are those compounds wherein R¹ is:

In some embodiments, for each of formula (I), (Ia) and (Ib), or apharmaceutically acceptable salt thereof, the group Z-L- is selectedfrom the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), or apharmaceutically acceptable salt thereof, the group Z-L- is selectedfrom the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), or apharmaceutically acceptable salt thereof, the group Z-L- is selectedfrom the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein each of R^(2a), R^(2b) andR^(2c) is independently selected from the group consisting of hydrogen,halogen, CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R^(2b) and R^(2c) are both Hand R^(2a) is selected from the group consisting of halogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₃ haloalkyl, —CN, —OMe and OEt. In some embodiments,R^(2b) and R^(2c) are both H and R^(2a) is halogen. In some embodiments,R^(2b) and R^(2c) are both H and R^(2a) is Cl.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R³ is NR^(g)R^(h). In someembodiments, R³ is selected from the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R³ is NR^(g)R^(h). In someembodiments, R³ is selected from the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R³ is NR^(g)R^(h). In someembodiments, R³ is selected from the group consisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R³ is —NR^(g)R^(h), and R^(h)combined with the N to which it is attached is a mono-, di- ortri-peptide comprising 1-3 natural amino acids and 0-2 non-natural aminoacids, wherein the non-natural aminoacids have an alpha carbonsubstituent selected from the group consisting of C₂₋₄ hydroxyalkyl,C₁₋₃ alkyl-guanidinyl, and C₁₋₄ alkyl-heteroaryl, the alpha carbon ofeach natural or non-natural amino acids are optionally furthersubstituted with a methyl group, and the terminal moiety of the mono-,di-, or tri-peptide is selected from the group consisting of C(O)OH,C(O)O—C₁₋₆ alkyl, and PO₃H₂.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein each natural amino acid ofR^(h) is independently selected from the group consisting of serine,alanine, glycine, lysine, argining, threonine, phenylalanine, tyrosine,asparatate, asparagine, histidine, and leucine.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R⁴ is selected from the groupconsisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R⁴ is selected from the groupconsisting of:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R⁴ is:

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein n is 0.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein R^(6a) and R^(6b) are eachindependently selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl and C₁₋₄ haloalkyl.

In some embodiments, for each of formula (I), (Ia) and (Ib), and thefurther selected embodiments above, the compounds or a pharmaceuticallyacceptable salt thereof, are those wherein

In addition to the compounds provided above, pharmaceutically acceptablesalts of those compounds are also provided. In some embodiments, thepharmaceutically acceptable salts are selected from ammonium, calcium,magnesium, potassium, sodium, zinc, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, hydrochloric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, acetic, propionic,isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, arginate, glucuronic acid and galactunoric acids. Insome embodiments, the pharmaceutically acceptable salts are selectedfrom ammonium, calcium, magnesium, potassium, sodium, hydrochloric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, acetic, propionic, isobutyric, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, arginate, glucuronicacid and galactunoric acids. In some embodiments, the pharmaceuticallyacceptable salts are sodium or hydrochloric.

In addition to salt forms, the present disclosure provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

An ester may be used as a prodrug for the corresponding carboxylic acid.A C₁₋₁₀ alkyl ester or a C₁₋₁₀ haloalkyl ester may be used as a prodrugfor the corresponding carboxylic acid. The following esters may be used:ter-butyl ester, methyl ester, ethyl ester, isopropyl ester. Morespecifically, ester prodrugs may be used as R³ groups such as threonineor serine prodrug esters which are linked to the rest of the moleculethrough their nitrogen. More specifically, the following prodrugs may beused for R³:

More specifically, the following prodrugs may be used for R³:

Pharmaceutical Compositions

In addition to the compounds provided herein, compositions of thosecompounds will typically contain a pharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In another embodiment, a pharmaceutical composition comprising acompound of the present disclosure including a compound of Formula (II),(IIa), (IIb), (I), (Ia), or (Ib) or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient, is provided.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. In some embodiments, the oneor more additional therapeutic agent is selected from the groupconsisting of an antimicrobial agent, an antiviral agent, a cytotoxicagent, a gene expression modulatory agent, a chemotherapeutic agent, ananti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent,an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, aradiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. In some embodiments, the one or moreadditional therapeutic agent is selected from the group consisting ofone or more of CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239,CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507,CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1,CCX3022 and CCX3384.

The pharmaceutical compositions for the administration of the compoundsof this disclosure may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self-emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to formosmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) of various average sizes (e.g., PEG400, PEG4000) andcertain surfactants such as cremophor or solutol, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such as mono- ordi-glycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present disclosure may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present disclosure are employed. As used herein,topical application is also meant to include the use of mouth washes andgargles.

The compounds of this disclosure may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thedisclosure may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe disclosure, the compound of the disclosure is coupled to a polymeror semipermeable polymer matrix that is formed as a stent or stent-graftdevice.

Methods of Treating Diseases and Disorders

The compounds of the disclosure may be used as immunomodulators. Thecompounds of the disclosure may be used as agonists, antagonists,partial agonists, inverse agonists, inhibitors of PD-1 and/or PD-L1 in avariety of contexts, both in vitro and in vivo. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the PD-1/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used as inhibitors of PD-L1. In some embodiments, thecompounds of the disclosure may be used as inhibitors of the CD80/PD-L1protein protein interaction. In some embodiments, the compounds of thedisclosure may be used to inhibit the interaction between PD-1 and PD-L1and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In someembodiments, the compounds of the disclosure may be used to inhibitVISTA and/or TIM-3. In some embodiments, the compounds of the disclosuremay be inhibitors of the PD-1/PD-L1 protein protein interaction andinhibitors of VISTA and/or TIM-3. In some embodiments, in addition tobeing inhibitors of the PD-1/PD-L1 protein protein interaction, thecompounds of the disclosure may be inhibitors of CTLA-4 and/or BTLAand/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/orCD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80.

The compounds of the disclosure may be contacted with the receptor theyinteract with, in aqueous solution and under conditions otherwisesuitable for binding of the ligand to the receptor. The receptor may bepresent in suspension (e.g., in an isolated membrane or cellpreparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the disclosure contacted withthe receptor should be sufficient to inhibit the PD-1/PD-L1 binding invitro as measured, for example, using an ELISA. The receptor may bepresent in solution or suspension, in a cultured or isolated cellpreparation or within a patient.

In some embodiments, the compounds of the present disclosure are usefulfor restoring and augmenting T cell activation. In some embodiments, thecompounds of the present disclosure are useful for enhancing an immuneresponse in a patient. In some embodiments, the compounds of the presentdisclosure are useful for treating, preventing, or slowing theprogression of diseases or disorders in a variety of therapeutic areas,such as cancer and infectious diseases.

In some embodiments, the compounds of the present disclosure can be usedfor treating patients suffering from conditions that are responsive toPD-1/PD-L1 protein protein interaction modulation.

In some embodiments, a method of modulating an immune response mediatedby the PD-1 signaling pathway in a subject, comprising administering tothe subject a therapeutically effective amount of a compound of thepresent disclosure including a compound of Formula (I), (Ia), (Ib),(II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof ora composition comprising a compound of Formula (I), (Ia), (Ib), (II),(IIa), or (IIb), or a pharmaceutically acceptable salt thereof, isprovided.

In some embodiments, a method of enhancing, stimulating, modulatingand/or increasing the immune response in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt thereof or a composition of a compound of the presentdisclosure including a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb), or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of inhibiting growth, proliferation, ormetastasis of cancer cells in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure including a compound of Formula (I),(Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable saltthereof or a composition of a compound of the present disclosureincluding a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, a method of treating a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of the present disclosure including a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt thereof or a composition of a compound of the presentdisclosure including a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb), or a pharmaceutically acceptable salt thereof, is provided.

In some embodiments, the subject suffers from a disease or disorderselected from the group consisting of an infectious disease, a bacterialinfectious disease, a viral infectious disease a fungal infectiousdisease, a solid tumor, a hematological malignancy, an immune disorder,an inflammatory disease, and cancer. In some embodiments, the disease ordisorder is selected from the group consisting of melanoma,glioblastoma, esophagus tumor, nasopharyngeal carcinoma, uveal melanoma,lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma,diffuse large B-cell lymphoma, primary mediastinal large B-celllymphoma, prostate cancer, castration-resistant prostate cancer, chronicmyelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma,synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, sarcoma of softtissue, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymusneoplasm, cancer of the thyroid gland, cancer of the parathyroid gland,uterine cancer, cancer of the adrenal gland, liver infection, Merkelcell carcinoma, nerve tumor, follicle center lymphoma, colon cancer,Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acuteleukemias including acute myeloid leukemia, chronic myeloid leukemia,acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiplemyeloma, ovary tumor, myelodysplastic syndrome, cutaneous or intraocularmalignant melanoma, renal cell carcinoma, small-cell lung cancer, lungcancer, mesothelioma, breast cancer, squamous non-small cell lung cancer(SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastriccancer, hepatocellular carcinoma, pancreatic carcinoma, pancreaticcancer, Pancreatic ductal adenocarcinoma, squamous cell carcinoma of thehead and neck, cancer of the head or neck, gastrointestinal tract,stomach cancer, HIV, Hepatitis A, Hepatitis B, Hepatitis C, hepatitis D,herpes viruses, papillomaviruses, influenza, bone cancer, skin cancer,rectal cancer, cancer of the anal region, testicular cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the urethra, cancer of the penis, cancer of thebladder, cancer of the kidney, cancer of the ureter, carcinoma of therenal pelvis, neoplasm of the central nervous system (CNS), tumorangiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma,epidermoid cancer, abestosis, carcinoma, adenocarcinoma, papillarycarcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cellcarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma,embryonal carcinoma, wilm's tumor, pleomorphic adenoma, liver cellpapilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma,leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma,lipoma and fibroma.

In some embodiments, a therapeutically effective amount of one or moreadditional therapeutic agents is further administered to the subject. Insome embodiments, the one or more additional therapeutic agents isselected from the group consisting of an antimicrobial agent, anantiviral agent, a cytotoxic agent, a gene expression modulatory agent,a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an immunotherapeutic agent, an anti-hormonal agent, ananti-fibrotic agent, radiotherapy, a radiotherapeutic agent, ananti-neoplastic agent, and an anti-proliferation agent. In someembodiments, the one or more additional therapeutic agent is selectedfrom the group consisting of one or more of CCX354, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025,CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, andCCX168-M1.

In some embodiments, the compounds of the present disclosure may be usedto inhibit an infectious disease. The infectious disease includes but isnot limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, thepathogenic infection by the virus Hepatitis (A, B, and C), herpes virus(e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus, pathogenicinfection by the bacteria chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, E. coli, legionella,diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax,plague, leptospirosis, and Lyme's disease bacteria, pathogenic infectionby the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.),Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), GenusMucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomycesdermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis andHistoplasma capsulatum, and pathogenic infection by the parasitesEntamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoebasp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosomacruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylusbrasiliensis.

In some embodiments, the compounds of the present disclosure may be usedto inhibit HIV infection, delay AIDS progression, deplete HIV viralreservoir or decrease the severity of symptoms or HIV infection andAIDS.

The compounds of the present disclosure may be used for the treatment ofcancers and precancerous conditions in a subject.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of thedisclosure are preferably administered to a patient (e.g., a human)intravenously, orally or topically. The effective amount may be anamount sufficient to modulate the PD-1/PD-L1 interaction and/or anamount sufficient to reduce or alleviate the symptoms presented by thepatient. Preferably, the amount administered is sufficient to yield aplasma concentration of the compound (or its active metabolite, if thecompound is a pro-drug) high enough to sufficient to modulate thePD-1/PD-L1 interaction. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Combinations

A concomitant medicine comprising the compounds of the presentdisclosure and other drug may be administered as a combinationpreparation in which both components are contained in a singleformulation, or administered as separate formulations. Theadministration by separate formulations includes simultaneousadministration and administration with some time intervals. In the caseof the administration with some time intervals, the compound of thepresent disclosure can be administered first, followed by another drugor another drug can be administered first, followed by the compound ofthe present disclosure. The administration method of the respectivedrugs may be the same or different.

The dosage of the other drug can be properly selected, based on a dosagethat has been clinically used. The compounding ratio of the compound ofthe present disclosure and the other drug can be properly selectedaccording to age and weight of a subject to be administered,administration method, administration time, disorder to be treated,symptom and combination thereof. For example, the other drug may be usedin an amount of 0.01 to 100 parts by mass, based on 1 part by mass ofthe compound of the present disclosure. The other drug may be acombination of two or more kind of arbitrary drugs in a properproportion.

The compounds described herein may be used or combined with one or moretherapeutic agent such as an antimicrobial agent, an antiviral agent, acytotoxic agent, a gene expression modulatory agent, a chemotherapeuticagent, an anti-cancer agent, an anti-angiogenic agent, animmunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent,radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and ananti-proliferation agent. These therapeutic agents may be in the formsof compounds, antibodies, polypeptides, or polynucleotides.

The compounds described herein may be used or combined with one or moreof a therapeutic antibody, a bispecific antibody and “antibody-like”therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus,an oncolytic virus, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), aCAR (chimeric antigen receptor) T-cell immunotherapeutic agent, or anycombination thereof.

Examples of chemotherapeutics include an alkylation agent, nitrosoureaagent, antimetabolite, anticancer antibiotics, vegetable-originalkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist,aromatase inhibitor, P-glycoprotein inhibitor, platinum complexderivative, other immunotherapeutic drugs and other anticancer drugs.

The compounds described herein may be used or combined with a cancertreatment adjunct, such as a leucopenia (neutropenia) treatment drug,thrombocytopenia treatment drug, antiemetic and cancer pain interventiondrug, concomitantly or in a mixture form.

The compounds described herein may be used or combined with a kinaseinhibitor.

In one embodiment, the compounds of the present disclosure can be usedwith other immunomodulators and/or a potentiating agent concomitantly orin a mixture form. Examples of the immunomodulator include variouscytokines, vaccines and adjuvants. Examples of these cytokines, vaccinesand adjuvants that stimulates immune responses include but not limitedto GM-CSF, M-CSF, G-CSF, interferon-a, beta, or gamma, IL-1, IL-2, IL-3,IL-12, Poly (I:C) and CPG. The potentiating agents includecyclophosphamide and analogs of cyclophosphamide, anti-TGF and imatinib(Gleevac), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent)or other antiangiogenic agents, an aromatase inhibitor, such asletrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesisinhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists,and IL-18 antagonists.

In some embodiments, the compounds described herein may be used orcombined with one or more modulator of CCR1, CCR2, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, themodulator is an antagonist.

In some embodiments, the compounds described herein may be used orcombined with one or more of CCX354, CCX9588, CCX140, CCX872, CCX598,CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX507, CCX430,CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, and CCX168-M1.

Dosage

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving the PD-1/PD-L1 interaction (about0.5 mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

In another aspect of the disclosure, the compounds of the disclosure canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. The compounds of the disclosure may also be used aspositive controls in assays for PD-1/PD-L1 interaction activity, i.e.,as standards for determining the ability of a candidate agent to bind toPD-1 and/or PD-L1, or as radiotracers for positron emission tomography(PET) imaging or for single photon emission computerized tomography(SPECT).

Also within the scope of the present disclosure are kits comprising acompound of the present disclosure or pharmaceutically acceptable saltsthereof and instructions for use. The kit can further contain at leastone additional reagent. Kits typically include a label indicating theintended use of the contents of the kit. The term label includes anywriting, or recorded material supplied on or with the kit, or whichotherwise accompanies the kit.

EXAMPLES

The following Examples illustrate various methods of making compounds ofthis disclosure including compounds of Formula (I), (Ia), or (Ib). Thefollowing examples are offered to illustrate, but not to limit theclaimed disclosure.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge. In the examples, a single m/z value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol or CH₃CN at 0.1 mg/mL and 1 microliter was infused with thedelivery solvent into the mass spectrometer, which scanned from 100 to1000 Daltons. All compounds could be analyzed in the positive ornegative ESI mode, using acetonitrile/water with 1% formic acid as thedelivery solvent.

The following abbreviations are used in the Examples and throughout thedescription of the disclosure: TLC means Thin layer chromatography.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisdisclosure, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed unless a specific enantiomer is specified.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1: Synthesis of(2S)-2-[[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoicAcid

Step a:

To a solution of 4-bromoindan-1-ol (12 g, 54 mmol) in THF (100 mL) wasadded N-ethyl-N-(propan-2-yl))propan-2-amine (50 mL, 290 mmol) and thesolution was cooled to 0° C. Methanesulfonyl chloride (5.0 mL, 65 mmol)was added dropwise, the cooling bath was removed, and the mixture wasstirred for an additional 2 h. Meanwhile, a separate flask was chargedwith ethyl 4-amino-5-chloro-2-ethoxybenzoate hydrochloride (13 g, 46mmol), cesium carbonate (18 g, 55 mmol), sodium iodide (8.0 g, 53 mmol),and DMF (100 mL). To this mixture was added the indanol preparation, andthe resulting mixture was stirred at 70° C. for 2 h. After cooling, thereaction mixture was filtered through a plastic fritted funnel and thefilter cake was washed with dichloromethane. Most of the solvent wasremoved under reduced pressure, with only 40 mL of DMF remaining. Theremaining mixture was taken up in ethyl acetate (200 mL) and water (200mL). The aqueous phase was discarded and the organic phase was washedwith brine and adsorbed onto silica gel (60 g). The mixture was purifiedby flash chromatography (6-12% EtOAc in hexane) to obtain crude ethyl4-[(4-bromoindan-1-yl)amino]-5-chloro-2-ethoxy-benzoate (960 mg). MS:(ES) m/z calculated for C₂₀H₂₂BrClNO₃ [M+H]⁺438.0, found 438.1.

Step b:

In a 40 mL vial was combined crude ethyl4-[(4-bromoindan-1-yl)amino]-5-chloro-2-ethoxy-benzoate (960 mg),2-flurophenylboronic acid (330 mg, 2.4 mmol),tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol), 2 Mpotassium carbonate (2 mL, 4 mmol), and 1,2-dimethoxyethane (8 mL). Themixture was degassed with a stream of nitrogen and stirred in the sealedvial at 80° C. for 1 h, after which the mixture was directly adsorbedonto silica gel and purified by flash chromatography to obtain 510 mg ofethyl 5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]benzoate.MS: (ES) m/z calculated for C₂₆H₂₅ClFNO₃ [M+H]⁺454.2, found 454.1.

Step c:

In a 40 mL vial, ethyl5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]benzoate (260mg, 0.57 mmol) was dissolved in THF (4 mL) and cooled to 0° C. To thissolution was added 1.0 M lithium aluminum hydride in THF (1.0 mL, 1.0mmol) and this mixture was stirred for 1 h, at which point sodiumsulfate decahydrate (1.0 g, 3.1 mmol) was added. The mixture was stirredfor 12 h, then purified by flash chromatography (0-20% EtOAc in hexane)to obtain[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methanol(57 mg, 24%). MS: (ES) m/z calculated for C₂₄H₂₃ClFNNaO₂ [M+Na]⁺434.1,found 434.1.

Step d:

To a solution of[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methanol(57 mg, 0.14 mmol) in dichloromethane (4 mL) cooled to 0° C. was addedN-ethyl-N-(propan-2-yl))propan-2-amine (0.10 mL, 0.57 mmol) andmethanesulfonyl chloride (0.020 mL, 0.26 mmol). The ice bath wasremoved, and the mixture was stirred for 1 h, at which point the mixturewas combined with L-serine methyl ester hydrochloride (213 mg, 1.4 mmol)and additional N-ethyl-N-(propan-2-yl))propan-2-amine (0.24 mL, 1.4mmol) and heated at 50° C. for Id. The crude reaction mixture wasdiluted with dichloromethane and washed with saturated sodiumbicarbonate solution. The organic phase was adsorbed onto silica gel andpurified by flash chromatography to obtain methyl(2S)-2-[[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoate(9 mg, 13%). MS: (ES) m/z calculated for C₂₈H₃₀ClFN₂NaO₄ [M+Na]⁺ 535.2,found 535.1.

Step e:

Methyl(2S)-2-[[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoate(9 mg, 0.018 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) andstirred with aqueous lithium hydroxide (1 mL) for 12 h. Solvent wasremoved under reduced pressure and the residue was taken up in methanoland acetic acid and purified by reverse phase preparative HPLC(CH₃CN—H₂O with 0.1% TFA) to obtain(2S)-2-[[5-chloro-2-ethoxy-4-[[4-(2-fluorophenyl)indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoicacid. The pure fractions were neutralized with sodium bicarbonate;acetonitrile was removed under reduced pressure, and the product wasextracted with 2:1 CHCl₃-2-propanol, dried with sodium sulfate, filteredand concentrated. The residue was lyophilized from acetonitrile-water toobtain a dry powder of the free form. MS: (ES) m/z calculated forC₂₇H₂₈ClFN₂NaO₄ [M+Na]⁺521.2, found 521.1. ¹H NMR (400 MHz, Methanol-d)δ 7.47-7.15 (m, 9H), 6.47 (d, J=2.4 Hz 1H), 5.27 (t, J=7.6 Hz, 1H),4.31-4.13 (m, 2H), 4.10-3.95 (m, 3H), 3.90-3.85 (m, 1H), 2.92-2.85 (m,2H), 2.65-2.56 (m, 1H), 2.04-1.94 (m, 1H), 1.41 (t, J=6.8 Hz, 3H).

Example 2:(2S)-2-[[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoicAcid

Step a:

Methyl 4-[(4-bromoindan-1-yl)amino]-5-chloro-2-ethoxy-benzoate wasprepared by a procedure similar to that used to prepare ethyl4-[(4-bromoindan-1-yl)amino]-5-chloro-2-ethoxy-benzoate. To a 40 mL vialwas added methyl 4-[(4-bromoindan-1-yl)amino]-5-chloro-2-ethoxy-benzoate(205 mg, 0.48 mmol),2-[3-(3-chloropropoxy)-2-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(194 mg, 0.62 mmol), tetrakis(triphenylphosphine)palladium (95 mg, 0.082mmol), 2 M potassium carbonate (0.75 mL, 1.5 mmol), and1,2-dimethoxyethane (7 mL). The mixture was thoroughly degassed withnitrogen and stirred at 80° C. for Id. The mixture was diluted withethyl acetate, washed with water, and adsorbed onto silica gel.Purification by flash chromatography (EtOAc-hexane) yielded 175 mgmethyl5-chloro-4-[[4-[3-(3-chloropropoxy)-2-methyl-phenyl]indan-1-yl]amino]-2-ethoxy-benzoate(69%).

Step b:

To a 40 mL vial containing methyl5-chloro-4-[[4-[3-(3-chloropropoxy)-2-methyl-phenyl]indan-1-yl]amino]-2-ethoxy-benzoate(175 mg, 0.33 mmol) dissolved in DMF (2 mL) was added 4-fluoropiperidinehydrochloride (135 mg, 0.96 mmol), sodium iodide (36 mg, 0.24 mmol), andpotassium carbonate (340 mg, 2.5 mmol). The mixture was sonnicatedbriefly, then stirred with heating at 70° C. for 2 h, then 80° C. for 2h. The mixture was taken up with 2:1 chloroform-2-propanol and water,and the organic phase was separated and adsorbed onto silica gel.Purification by flash chromatography (2-20% methanol in dichloromethane)provided methyl5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]benzoatein quantitative yield, which was carried on to the next step withoutcharacterization. The residue was dissolved in THF (2 mL) and added to asuspension of lithium aluminum hydride (50 mg, 1.3 mmol) suspended inTHF (2 mL) that had been cooled to 0° C. Afterwards, the ice bath wasremoved and the slurry was stirred at room temperature for 1 h and 45°C. for 30 m. The reaction was quenched by carerful addition of a minimalamount of water and magnesium sulfate and purified by flashchromatography (4-100% acetone in hexane) to obtain[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methanol(51 mg, 27%, 2 steps). MS: (ES) m/z calculated for C₃₃H₄₁ClFN₂O₃ [M+H]⁺567.3, found 567.5.

Step c:

To a solution of obtain[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methanol(51 mg, 0.090 mmol) in THF (2 mL) and cooled to 0° C. was addedN-ethyl-N-(propan-2-yl))propan-2-amine (0.10 mL, 0.57 mmol) andmethanesulfonyl chloride (0.040 mL, 0.52 mmol). The ice bath was removedand the mixture was stirred at room temperature. After 90 m, thismixture was added to a solution of L-serinie methyl ester hydrochloride(150 mg, 0.96 mmol) and N-ethyl-N-(propan-2-yl))propan-2-amine (0.17 mL,0.98 mmol) in DMF (2 mL) and stirred at 70° C. for 16 h. The mixture wastaken up in 2:1 chloroform-2-propanol and water, and the organic phasewas separated, adsorbed onto silica gel, and purified by flashchromatography (2-80% ethanol in toluene) to obtain methyl(2S)-2-[[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoate. MS: (ES) m/z calculated for C₃₇H₄₇ClFN₃NaO₅[M+Na]⁺ 690.3, found 690.5.

Step d:

To an 8 mL vial containing a solution of methyl(2S)-2-[[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoatedissolved in THF (0.60 mL) and methanol (0.60 mL) was added a solutionof lithium hydroxide monohydrate (25 mg, 0.60 mmol) in water (0.60 mL).After stirring for 30 m, LCMS indicated hydrolysis of the ester wascomplete. The mixture was acidified with acetic acid and purified byreverse phase preparative HPLC (CH₃CN—H₂O with 0.1% TFA) to provide(2S)-2-[[5-chloro-2-ethoxy-4-[[4-[3-[3-(4-fluoro-1-piperidyl)propoxy]-2-methyl-phenyl]indan-1-yl]amino]phenyl]methylamino]-3-hydroxy-propanoicacid as the bis trifluoroacetate salt. MS: (ES) m/z calculated forC₃₆H₄₆ClFN₃O₅[M+H]⁺ 654.3, found 654.3. ¹H NMR (400 MHz, Methanol-d) S7.33-7.25 (m, 3H), 7.20 (t, J=8.0 Hz, 1H), 7.06 (d, J=6.0 Hz, 1H), 6.95(d, J=8.4 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.53 (d, J=20 Hz, 1H),5.31-5.19 (m, 1H), 5.00 (d, J=48 Hz, 1H), 4.29 (d, J=13 Hz, 1H),4.21-4.13 (m, 3H), 4.13-3.96 (m, 4H), 3.91 (br s, 1H), 3.76-3.53 (m,2H), 3.46-3.37 (m, 2H), 2.78-2.53 (m, 3H), 2.41-2.20 (m, 4H), 2.18-2.09(m, 1H), 2.08-1.86 (m, 5H), 1.43 (t, J=6.8 Hz, 3H).

Compounds in Table 1 were prepared by methods as described in theExamples, and evaluated according to the assay below. The IC₅₀ of thecompounds are presented in Table 1 as follows:

+, 20000 nM≥IC₅₀≥500 nM;++, 500 nM≥IC₅₀≥5 nM;+++, 5 nM>IC₅₀.

Characterization Conditions

Reverse phase HPLC conditions used for determination of retention timesin Table 1: Column: ZORBAX (SB-C18 2.1×50 mm, 5 μm)

Mobile phase A: 95% H₂O, 5% MeCN (with 0.1% Formic Acid)

Mobile phase B: 5% H₂O, 95% MeCN (with 0.1% Formic Acid)

Flow rate: 1.0 mL/min

Gradient: 20 to 100% B in 3.5 min

Biological Example: Enzyme-Linked Immunosorbent Assay—ELISA

Plates were coated with 1 μg/mL of human PD-L1 (obtained from R&D) inPBS overnight at 4° C. The wells were then blocked with 2% BSA in PBS(W/V) with 0.05% TWEEN-20 for 1 hour at 37° C. The plates were washed 3times with PBS/0.05% TWEEN-20 and the samples were diluted to 1:5 indilution medium in the ELISA plates. Human PD-1 and biotin 0.3 μg/mL(ACRO Biosystems) were added and incubated for 1 hour at 37° C. thenwashed 3 times with PBS/0.05% TWEEN-20. A second block was added with 2%SA in PBS (W/V)/0.05% TWEEN-20 for 10 min at 37° C. and was washed 3times with PBS/0.05% TWEEN-20. Streptavidin-HRP was added for 1 hour at37° C. then washed 3 times with PBS/0.05% TWEEN-20. TMB substrate wasadded and reacted for 20 min at 37° C. A stop solution (2 N aqueousH₂SO₄) was added. The absorbance was read at 450 nm using a micro-platespectrophotometer. The results are shown in Table 1.

TABLE 1 ELISA RP- IC₅₀ MS HPLC Structure (nM) [M + H]⁺ R_(t) (min)

++ 663.3 1.87

+ 663.3 1.69

++ 677.2 1.78

+ 677.2 1.72

+ 684.2 2.51

+ 697.2 1.67

++ 652.2 1.99

++ 521.1 [M + Na] 2.88

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, or a prodrug orbioisostere thereof; wherein: R¹ is selected from Formula (IIa) orFormula (IIb):

each of substitutents R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) isindependently selected from the group consisting of H, halogen, —CN,—R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a), —OC(O)NR^(a)R^(b),—NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c), —NR^(a)—C(O)NR^(a)R^(b),—NR^(a)R^(b), —OR^(a), —O—X¹—OR^(a), —O—X¹—CO₂R^(a),—O—X¹—CONR^(a)R^(b), —X¹—OR^(a), —X¹—NR^(a)R^(b), —X¹—CO₂R^(a),—X¹—CONR^(a)R^(b), —SF₅, and —S(O)₂NR^(a)R^(b), wherein each X¹ is aC₁₋₄ alkylene; each R^(a) and R^(b) is independently selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the samenitrogen atom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, wherein the five or six-membered ringis optionally substituted with oxo; each R^(c) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl andC₁₋₈ haloalkyl; and optionally when two substituents are on adjacentcarbon atoms of the benzene ring, they may combine to form a fused five,six or seven-membered carbocyclic or heterocyclic ring optionallysubstituted with from 1 to 3 substituents independently selected fromhalo, oxo, C₁₋₈ haloalkyl and C₁₋₈ alkyl; L is a linking group selectedfrom the group consisting of:

wherein each of the subscripts q is independently 1, 2, 3 or 4, and L isoptionally further substituted with one or two members selected from thegroup consisting of halogen, hydroxy, C₁₋₃ alkyl, —O—C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H; Z is selected from the groupconsisting of azetidinyl, pyrollidinyl, piperidinyl, morpholinyl,pyridyl, pyrimidinyl, guanidinyl, quinuclidine, and8-azabicyclo[3.2.1]octane, each of which is optionally substituted withfrom 1 to 3 groups independently selected from halogen, hydroxy, C₁₋₃alkyl, —NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)₂, —O—C₁₋₃ alkyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl and —CO₂H; or Z is selected from the groupconsisting of —CO₂R^(z1) and —NR^(Z1)R^(z2); wherein R^(z1) is selectedfrom the group consisting of H, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₁₋₈hydroxyalkyl; and R^(z2) is selected from —C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₁₋₈ alkyl-COOH, C₁₋₈ alkyl-OH, C₁₋₈ alkyl-CONH₂, C₁₋₈ alkyl-SO₂NH₂,C₁₋₈ alkyl-PO₃H₂, C₁₋₈ alkyl-C(O)NHOH, —C(O)—C₁₋₈alkyl-OH,—C(O)—C₁₋₈alkyl-COOH, C₃₋₁₀ cycloalkyl, —C₃₋₁₀ cycloalkyl-COOH, —C₃₋₁₀cycloalkyl-OH, C₄₋₈ heterocyclyl, —C₄₋₈ heterocyclyl-COOH, —C₄₋₈heterocyclyl-OH, —C₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀cycloalkyl, C₅₋₁₀ heteroaryl and —C₁₋₈alkyl-C₅₋₁₀ heteroaryl; eachR^(2a), R^(2b) and R^(2c) is independently selected from the groupconsisting of H, halogen, —CN, —R^(d), —CO₂R^(e), —CONR^(e)R^(f),—OC(O)NR^(e)R^(f), —NR^(f)C(O)R^(e), —NR^(f)C(O)₂R^(d),—NR^(e)—C(O)NR^(e)R^(f), —NR^(e)R^(f), —OR^(e), —X²—OR^(e),—X²—NR^(e)R^(f), —X²—CO₂R^(e), —SF₅, and —S(O)₂NR^(e)R^(f), wherein eachX² is a C₁₋₄ alkylene; each R^(e) and R^(f) is independently selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to thesame nitrogen atom can be combined with the nitrogen atom to form a fiveor six-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O and S, and optionally substituted with oxo;each R^(d) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; R³ is selected from the groupconsisting of —NR^(g)R^(h) and C₄₋₁₂ heterocyclyl, wherein the C₄₋₁₂heterocyclyl is optionally substituted with 1 to 6 R^(3a); each R^(3a)is independently selected from the group consisting of halogen, —CN,—R^(i), —CO₂R^(j), —CONR^(j)R^(k), —CONHC₁₋₆ alkyl-OH, —C(O)R^(j),—OC(O)NR^(j)R^(k), —NR^(j)C(O)R^(k), —NR^(j)C(O)₂R^(k), —CONHOH, —PO₃H₂,—NR^(j)—X³—C(O)₂R^(k), —NR^(j)C(O)NR^(j)R^(k), —NR^(j)R^(k), —OR^(j),—S(O)₂NR^(j)R^(k), —O—X³—OR, —O—X³—NR^(j)R^(k), —O—X³—CO₂R^(j),—O—X³—CONR^(j)R^(k), —X³—OR^(j), —X³—NR^(j)R^(k), —X³—CO₂R^(j),—X³—CONR^(j)R^(k), —X³—CONHSO₂R^(j) and SF₅; wherein X³ is C₁₋₆ alkyleneand is optionally further substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, COO—C—₁₋₈alkyl or CO₂H, wherein each R^(j) and R^(k) isindependently selected from hydrogen, C₁₋₈ alkyl optionally substitutedwith 1 to 2 substituents selected from OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, COO—C₁₋₈alkyl or CO₂H, and C₁₋₈ haloalkyl optionally substitutedwith 1 to 2 substituents selected from OH, SO₂NH₂, CONH₂, C(O)NHOH,PO₃H₂, COO—C₁₋₈alkyl or CO₂H, or when attached to the same nitrogen atomR^(j) and R^(k) can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(i) is independently selected from the group consisting of —OH,C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl each of which may beoptionally substituted with OH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,COO—C₁₋₈-alkyl or CO₂H; R^(g) is selected from the group consisting ofH, C₁₋₈ haloalkyl and C₁₋₈ alkyl; R^(h) is selected from —C₁₋₈ alkyl,C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C₁₋₈alkyl-CO₂R^(j),C₁₋₈alkyl-CONR^(j)R^(k), and C₁₋₈alkyl-CONHSO₂ ^(j)R, C₁₋₈alkyl-SO₂NR^(j)R^(k), C₁₋₈ alkyl-PO₃H₂, C₁₋₈ alkyl-C(O)NHOH, C₁₋₈alkyl-NR^(h1)R^(h2), —C(O)R, C₃₋₁₀ cycloalkyl, —C₃₋₁₀cycloalkyl-COOR^(j), —C₃₋₁₀ cycloalkyl-OR^(j), C₄₋₈ heterocyclyl, —C₄₋₈heterocyclyl-COOR^(j), —C₄₋₈ heterocyclyl-OR^(j), —C₁₋₈ alkyl-C₄₋₈heterocyclyl, —C(═O)OC₁₋₈ alkyl-C₄₋₈ heterocyclyl, —C₁₋₈ alkyl-C₃₋₁₀cycloalkyl, C₅₋₁₀ heteroaryl, —C₁₋₈alkyl-C₅₋₁₀ heteroaryl, —C₁₋₈alkyl-C₆₋₁₀ aryl, —C₁₋₈ alkyl-(C═O)—C₆₋₁₀ aryl, —CO₂—C₁₋₈ alkyl-O₂C—C₁₋₈alkyl, —C₁₋₈ alkyl-NH(C═O)—C₂₋₈ alkenyl, —C₁₋₈ alkyl-NH(C═O)—C₁₋₈ alkyl,—C₁₋₈ alkyl-NH(C═O)—C₂₋₈ alkynyl, —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈alkyl-COOR^(j), and —C₁₋₈ alkyl-(C═O)—NH—C₁₋₈ alkyl-OR^(j) optionallysubstituted with CO₂H; or R^(h) combined with the N to which it isattached is a mono-, di- or tri-peptide comprising 1-3 natural aminoacids and 0-2 non-natural amino acids, wherein the non-naturalaminoacids have an alpha carbon substituent selected from the groupconsisting of C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl-guanidinyl, and C₁₋₄alkyl-heteroaryl, the alpha carbon of each natural or non-natural aminoacids are optionally further substituted with a methyl group, and theterminal moiety of the mono-, di-, or tri-peptide is selected from thegroup consisting of C(O)OH, C(O)O—C₁₋₆ alkyl, and PO₃H₂, wherein R^(h1)and R^(h2) are each independently selected from the group consisting ofH, C₁₋₆ alkyl, and C₁₋₄ hydroxyalkyl; the C₁₋₈ alkyl portions of R^(h)are optionally further substituted with from 1 to 3 substituentsindependently selected from OH, COOH, SO₂NH₂, CONH₂, C(O)NHOH, COO—C₁₋₈alkyl, PO₃H₂ and C₅₋₆ heteroaryl optionally substituted with 1 to 2 C₁₋₃alkyl substituents, the C₅₋₁₀ heteroaryl and the C₆₋₁₀ aryl portions ofR^(h) are optionally substituted with 1 to 3 substituents independentlyselected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, C(O)NHOH, PO₃H₂,COO—C₁₋₈alkyl, C₁₋₄alkyl, C₁₋₄alkyl-OH, C₁₋₄alkyl-SO₂NH₂, C₁₋₄alkylCONH₂, C₁₋₄alkyl-C(O)NHOH, C₁₋₄alkyl-PO₃H₂, C₁₋₄alkyl-COOH and phenyl,and the C₄₋₈ heterocyclyl and C₃₋₁₀ cycloalkyl portions of R^(h) areoptionally substituted with 1 to 4 R^(w) substituents; each R^(w)substituent is independently selected from C₁₋₄ alkyl, C₁₋₄ alkyl-OH,C₁₋₄ alkyl-COOH, C₁₋₄ alkyl-SO₂NH₂, C₁₋₄ alkyl CONH₂, C₁₋₄alkyl-C(O)NHOH, C₁₋₄ alkyl-PO₃H, OH, COO—C₁₋₈ alkyl, COOH, SO₂NH₂,CONH₂, C(O)NHOH, PO₃H₂ and oxo; R⁴ is selected from the group consistingof O—C₁₋₈ alkyl, O—C₁₋₈ haloalkyl, C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, —O—C₁₋₄alkyl-C₄₋₇ heterocycloalkyl, —O—C₁₋₄ alkyl-C₆₋₁₀aryl and —O—C₁₋₄alkyl-C₅₋₁₀ heteroaryl, each of which is optionally substituted with 1to 5 R^(4a); each R^(4a) is independently selected from the groupconsisting of halogen, —CN, —R^(m), —CO₂R^(n), —CONR^(n)R^(p),—C(O)R^(n), —OC(O)NR^(n)R^(p), —NR^(n)C(O)R^(P), —NR^(n)C(O)₂R^(m),—NR^(n)—C(O)NR^(n)R^(p), —NR^(n)R^(P), —OR^(n), —O—X⁴—OR^(n),—O—X⁴—NR^(n)R^(P), —O—X⁴—CO₂R^(n), —O—X⁴—CONR^(n)R^(P), —X⁴—OR^(n),—X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n), —X⁴—CONR^(n)R^(p), —SF₅,—S(O)₂R^(n)R^(p), —S(O)₂NR^(n)R^(p), C₃₋₇ cycloalkyl and C₄₋₇heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings areoptionally substituted with 1 to 5 R^(t), wherein each R^(t) isindependently selected from the group consisting of C₁₋₈ alkyl,C₁₋₈haloalkyl, —CO₂R^(n), —CONR^(n)R^(p), —C(O)R^(n), —OC(O)NR^(n)R^(p),—NR^(n)C(O)R^(P), —NR^(n)C(O)₂R^(m), —NR^(n)—C(O)NR^(n)R^(p),—NR^(n)R^(p), —OR^(n), —O—X⁴—OR^(n), —O—X⁴—NR^(n)R^(P), —O—X⁴—CO₂R^(n),—O—X⁴—CONR^(n)R^(P), —X⁴—OR^(n), —X⁴—NR^(n)R^(p), —X⁴—CO₂R^(n),—X⁴—CONR^(n)R^(p), —SF₅, and —S(O)₂NR^(n)R^(p); wherein each X⁴ is aC₁₋₆ alkylene; each R^(n) and R^(P) is independently selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the samenitrogen atom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(m) is independently selected from the group consisting of C₁₋₈alkyl, C₂₋₈ alkenyl, and C₁₋₈ haloalkyl; and optionally when two R^(4a)substituents are on adjacent atoms, they are combined to form a fusedfive or six-membered carbocyclic or heterocyclic ring optionallysubstituted with oxo; the subscript n is 0, 1, 2 or 3; each R⁵ isindependently selected from the group consisting of halogen, —CN,—R^(q), —CO₂R^(r), —CONR^(r)R^(s), —C(O)R^(r), —OC(O)NR^(r)R^(s),—NR^(r)C(O)R^(s), —NR^(r)C(O)₂R^(q), —NR^(r)—C(O)NR^(r)R^(s),—NR^(r)R^(s), —OR^(r), —O—X⁵—OR^(r), —O—X⁵—NR^(r)R^(s), —O—X⁵—CO₂R^(r),—O—X⁵—CONR^(r)R^(s), —X⁵—OR^(r), —X⁵—NR^(r)R^(s), —X⁵—CO₂R^(r),—X⁵—CONR^(r)R^(s), —SF₅, —S(O)₂NR^(r)R^(s), wherein each X⁵ is a C₁₋₄alkylene; each R^(r) and R^(s) is independently selected from hydrogen,C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogenatom can be combined with the nitrogen atom to form a five orsix-membered ring having from 0 to 2 additional heteroatoms as ringmembers selected from N, O or S, and optionally substituted with oxo;each R^(q) is independently selected from the group consisting of C₁₋₈alkyl, and C₁₋₈ haloalkyl; R^(6a) is selected from the group consistingof H, C₁₋₄ alkyl and C₁₋₄ haloalkyl; the subscript m is 0, 1, 2, 3 or 4;each R^(6b) is independently selected from the group consisting of F,C₁₋₄ alkyl, O—R^(u), C₁₋₄ haloalkyl, NR^(u)R^(v), wherein each R^(u) andR^(v) is independently selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈haloalkyl, or when attached to the same nitrogen atom can be combinedwith the nitrogen atom to form a five or six-membered ring having from 0to 2 additional heteroatoms as ring members selected from N, O or S, andoptionally substituted with oxo.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof having the formula (Ia)


3. The compound of claim 1, or a pharmaceutically acceptable saltthereof having the formula (Ib)


4. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group R¹ is selected from the group consisting of:


5. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group R¹ is selected from the group consisting of:


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group R¹ is:


7. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group Z-L- is selected from the group consisting of:


8. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group Z-L- is selected from the group consisting of:


9. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein the group Z-L- is selected from the group consisting of:


10. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein each of R^(2a), R^(2b) and R^(2c) is independentlyselected from the group consisting of hydrogen, halogen, CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl.
 11. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof wherein R³ is —NR^(g)R^(h).
 12. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof wherein R³ isselected from the group consisting of:


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein R³ is selected from the group consisting of:


14. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein R³ is selected from the group consisting of:


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein R⁴ is selected from the group consisting of:


16. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein R⁴ is selected from the group consisting of:


17. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein R⁴ is selected from the group consisting of:


18. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein n is
 0. 19. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(6a) and R^(6b) areeach independently selected from the group consisting of hydrogen,halogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl.
 20. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein


21. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 22. The pharmaceutical composition of claim 21,further comprising one or more additional therapeutic agents. 23.(canceled)
 24. A method of modulating an immune response mediated by thePD-1 signaling pathway in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof.
 25. A method of enhancing,stimulating, modulating and/or increasing the immune response in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of claim 1, or a pharmaceuticallyacceptable salt thereof.
 26. A method of inhibiting growth,proliferation, or metastasis of cancer cells in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 27. A method of treating a subject sufferingfrom or susceptible to a disease or disorder mediated by the PD-1signaling pathway, comprising administering to the subject atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 28. (canceled)
 29. The methodof claim 27, wherein the disease or disorder is selected from the groupconsisting of melanoma, glioblastoma, esophagus tumor, nasopharyngealcarcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNSlymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primarymediastinal large B-cell lymphoma, prostate cancer, castration-resistantprostate cancer, chronic myelocytic leukemia, Kaposi's sarcomafibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma,rhabdomyosarcoma, sarcoma of soft tissue, sarcoma, sepsis, biliarytumor, basal cell carcinoma, thymus neoplasm, cancer of the thyroidgland, cancer of the parathyroid gland, uterine cancer, cancer of theadrenal gland, liver infection, Merkel cell carcinoma, nerve tumor,follicle center lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin'slymphoma, leukemia, chronic or acute leukemias including acute myeloidleukemia, chronic myeloid leukemia, acute lymphoblastic leukemia,chronic lymphocytic leukemia, multiple myeloma, ovary tumor,myelodysplastic syndrome, cutaneous or intraocular malignant melanoma,renal cell carcinoma, small-cell lung cancer, lung cancer, mesothelioma,breast cancer, squamous non-small cell lung cancer (SCLC), non-squamousNSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellularcarcinoma, pancreatic carcinoma, pancreatic cancer, Pancreatic ductaladenocarcinoma, squamous cell carcinoma of the head and neck, cancer ofthe head or neck, gastrointestinal tract, stomach cancer, HIV, HepatitisA, Hepatitis B, Hepatitis C, hepatitis D, herpes viruses,papillomaviruses, influenza, bone cancer, skin cancer, rectal cancer,cancer of the anal region, testicular cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, cancer of the esophagus, cancerof the small intestine, cancer of the endocrine system, cancer of theurethra, cancer of the penis, cancer of the bladder, cancer of thekidney, cancer of the ureter, carcinoma of the renal pelvis, neoplasm ofthe central nervous system (CNS), tumor angiogenesis, spinal axis tumor,brain stem glioma, pituitary adenoma, epidermoid cancer, abestosis,carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma,bronchogenic carcinoma, renal cell carcinoma, transitional cellcarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm's tumor,pleomorphic adenoma, liver cell papilloma, renal tubular adenoma,cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma,lymphangioma, osteoma, chondroma, lipoma and fibroma. 30-31. (canceled)